The influence of gender on metabolic activity of enzymatic system of cytochrome P450 in the model of isolated perfused rat liver.
| Authors | |
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| Year of publication | 2006 |
| Type | Article in Proceedings |
| Conference | New Frontiers in the Research of PhD students |
| MU Faculty or unit | |
| Citation | |
| Field | Pharmacology and pharmaceutical chemistry |
| Keywords | cytochrome P450; gender; isolated perfused liver |
| Description | Interindividual variability of activity of oxidative and conjugating enzymes, especially the system of cytochrome P450, can be based on many different factors i.e. gender, age, genetic factors or interactions between simultaneously applied drugs. Such a variability may result in a different pharmacoterapeutical effectivity, adverse effects or toxicity of apllied drug. A suitable model for investigations on the activity of hepatic CYPs 450 and biotransformation processes is represented by the isolated perfused liver. The main advantage of this model, in comparison with other methods used for measuring the CYP activity, are conditions resembling physiological situation in the organism. High correlations between results obtained on the model of isolated perfused liver and results from the whole organism were confirmed by many comparative studies. The histologic microstructure is intact as well as the system of biochemical and physiological mechanisms. On the basis of previous studies we can declare a high level of homology between rat and human subfamilies of CYP 450 1A and 2E. Such similarity is also present in subfamilies 2D and 3A (Guengerich, 1997). CYP enzymes comprise a large family of hemoprotein, and enzymes from three subfamilies (CYP 2C, CYP 2D and CYP 3A) are mainly involved in biotransformation of xenobiotics in both human and rats. Cytochrome P-450 from rats was one of the first isolated and characterized. We studied the influence of gender on selected isoenzymes using the following drugs as specific markers: tolbutamide for CYP 2C6, dextromethorphan for CYP 2D2 and midazolam for CYP 3A2 (Kobayashi et al., 2002, Dostalek et al. 2003). CYP2D2 activity in rat females was significantly higher than in males. Also the final concentration of a marker metabolite (dextrorphan) in females was higher only in CYP2D2. The elevation was 10% in the 60th min and 9% in the 120th min. In contrast activity in CYP subfamily in females was lower than in males. All last three isoforms of CYP450, CYP2C6 (tolbutamid) and CYP1A2 (phenacetin), showed lower activity when compared to CYP2D2, and female metabolization rate was slower than in males. As we expected, the activity of CYP subfamilies differed due to gender. CYP 2D2 activity in rat females was significantly higher than in males (Fig. 1). Also the final concentration of a marker metabolite (dextrorphan) in females was higher only in CYP 2D2. The elevation was 5,7% in the 30th min, 33% in the 60th min and 34% in the 120th min. In contrast activity in CYP 3A subfamily in females was lower than in males. Next two isoforms of CYP450, used as markers were tolbutamid (CYP2C6 – metabolite 4-hydroxytolbutamid) and phenacetin (CYP1A2 – metabolite paracetamol). They showed dramatically lower activity when compared to CYP 2D2, and female metabolization was slower than in males. Thus, the obtained results suggest that the activity of CYP 450 is gender dependent and different dosing schemes for males and females should be used when administering drugs metabolized by CYP 450. |
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